HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use INOmax
`safely and effectively. See full prescribing information for INOmax.
`
`INOmax (nitric oxide) for inhalation
`Initial U.S. Approval: 1999
`
`
`
`_________________ INDICATIONS AND USAGE__________________
`INOmax is a vasodilator, which, in conjunction with ventilatory support and
`other appropriate agents, is indicated for the treatment of term and near-term
`(>34 weeks gestation) neonates with hypoxic respiratory failure associated
`with clinical or echocardiographic evidence of pulmonary hypertension,
`where it improves oxygenation and reduces the need for extracorporeal
`membrane oxygenation (1.1).
`
`Monitor for PaO2, methemoglobin, and inspired NO2 during INOmax
`administration (1.1).
`
`Utilize additional therapies to maximize oxygen delivery (1.1).
`
`______________ DOSAGE AND ADMINISTRATION ______________
`Dosage: The recommended dose of INOmax is 20 ppm, maintained for up to
`14 days or until the underlying oxygen desaturation has resolved (2.1).
`
`Administration:
`•
`INOmax must be delivered via a system which does not cause
`generation of excessive inhaled nitrogen dioxide (2.2).
`•
`Do not discontinue INOmax abruptly (2.2).
`_____________ DOSAGE FORMS AND STRENGTHS______________
`INOmax (nitric oxide) is a gas available in 100 ppm and 800 ppm
`concentrations.
`
`
`
`
`
`
`
`
`2
`
`2.1
`2.2
`3
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`1
`INDICATIONS AND USAGE
`Treatment of Hypoxic
`1.1
`Respiratory Failure
`DOSAGE AND
`ADMINISTRATION
`Dosage
`Administration
`DOSAGE FORMS AND
`STRENGTHS
`CONTRAINDICATIONS
`WARNINGS AND
`PRECAUTIONS
`Rebound
`Methemoglobinemia
`Elevated NO2 Levels
`ADVERSE REACTIONS
`Clinical Trials Experience
`Post-Marketing Experience
`
`4
`5
`
`5.1
`5.2
`5.3
`6
`6.1
`6.2
`
`____________________ CONTRAINDICATIONS____________________
`Neonates known to be dependent on right-to-left shunting of blood (4).
`
`_______________ WARNINGS AND PRECAUTIONS _______________
`Rebound: Abrupt discontinuation of INOmax may lead to worsening
`oxygenation and increasing pulmonary artery pressure (5.1).
`
`Methemoglobinemia: Methemoglobin increases with the dose of nitric oxide;
`following discontinuation or reduction of nitric oxide, methemoglobin levels
`return to baseline over a period of hours (5.2).
`
`Elevated NO2 Levels: NO2 levels should be monitored (5.3).
`
`Heart Failure: In patients with pre-existing left ventricular dysfunction, inhaled
`nitric oxide may increase pulmonary capillary wedge pressure leading to
`pulmonary edema (5.4).
`
`____________________ ADVERSE REACTIONS ____________________
`Methemoglobinemia and elevated NO2 levels are dose dependent adverse
`events. Worsening oxygenation and increasing pulmonary artery pressure
`occur if INOmax is discontinued abruptly. Other adverse reactions that
`occurred in more than 5% of patients receiving INOmax in the CINRGI study
`were: thrombocytopenia, hypokalemia, bilirubinemia, atelectasis, and
`hypotension (6).
`To report SUSPECTED ADVERSE REACTIONS, contact INO
`Therapeutics at 1-877-566-9466 and http://www.inomax.com/ or FDA at
`1-800-FDA-1088 or www.fda.gov/medwatch.
`
`____________________ DRUG INTERACTIONS ____________________
`Nitric oxide donor agents: Nitric oxide donor compounds, such as prilocaine,
`sodium nitroprusside, and nitroglycerin, when administered as oral, parenteral,
`or topical formulations, may have an additive effect with INOmax on the risk
`of developing methemoglobinemia (7).
`
`
`Revised: 12/2010
`
`7
`8
`
`8.1
`8.2
`8.3
`8.4
`8.5
`10
`11
`12
`
`12.1.
`12.2.
`12.3.
`12.4
`
`12.5
`
`DRUG INTERACTIONS
`USE IN SPECIFIC
`POPULATIONS
`Pregnancy
`Labor and Delivery
`Nursing Mothers
`Pediatric Use
`Geriatric Use
`OVERDOSAGE
`DESCRIPTION
`CLINICAL
`PHARMACOLOGY
`Mechanism of Action
`Pharmacodynamics
`Pharmacokinetics
`Pharmacokinetics: Uptake and
`Distribution
`Pharmacokinetics: Metabolism
`
`Reference ID: 2881485
`
`

`

`12.6
`13
`
`13.1.
`
`14
`14.1
`
`Pharmacokinetics: Elimination
`NONCLINICAL
`TOXICOLOGY
`Carcinogenesis, Mutagenesis,
`Impairment of Fertility
`CLINICAL STUDIES
`Treatment of Hypoxic
`Respiratory Failure (HRF)
`
`14.2
`
`14.3
`
`15.
`16
`
`Ineffective in Adult Respiratory
`Distress Syndrome (ARDS)
`Ineffective in Prevention of
`Bronchopulmonary Dysplasia
`(BPD)
`REFERENCES
`HOW SUPPLIED/STORAGE
`AND HANDLING
`
`
`*Sections or subsections omitted from the full prescribing information are not listed.
`
`
`
`
`Reference ID: 2881485
`
`

`

`FULL PRESCRIBING INFORMATION
`
`INDICATIONS AND USAGE
`
` 1
`
`
`
`
`
`Treatment of Hypoxic Respiratory Failure
`1.1
`INOmax® is a vasodilator, which, in conjunction with ventilatory support and other appropriate
`agents, is indicated for the treatment of term and near-term (>34 weeks) neonates with hypoxic
`respiratory failure associated with clinical or echocardiographic evidence of pulmonary
`hypertension, where it improves oxygenation and reduces the need for extracorporeal membrane
`oxygenation.
`
`Utilize additional therapies to maximize oxygen delivery. In patients with collapsed alveoli,
`additional therapies might include surfactant and high-frequency oscillatory ventilation.
`
`The safety and effectiveness of inhaled nitric oxide have been established in a population
`receiving other therapies for hypoxic respiratory failure, including vasodilators, intravenous
`fluids, bicarbonate therapy, and mechanical ventilation. Different dose regimens for nitric oxide
`were used in the clinical studies [see Clinical Studies (14)].
`
`Monitor for PaO2, methemoglobin, and inspired NO2 during INOmax administration.
`
`DOSAGE AND ADMINISTRATION
`
` 2
`
`
`
`
`
`Dosage
`2.1
`Term and near-term neonates with hypoxic respiratory failure
`The recommended dose of INOmax is 20 ppm. Treatment should be maintained up to 14 days or
`until the underlying oxygen desaturation has resolved and the neonate is ready to be weaned
`from INOmax therapy.
`
`An initial dose of 20 ppm was used in the NINOS and CINRGI trials. In CINRGI, patients
`whose oxygenation improved with 20 ppm were dose-reduced to 5 ppm as tolerated at the end of
`4 hours of treatment. In the NINOS trial, patients whose oxygenation failed to improve on 20
`ppm could be increased to 80 ppm, but those patients did not then improve on the higher dose.
`
`Reference ID: 2881485
`
`

`

`As the risk of methemoglobinemia and elevated NO2 levels increases significantly when
`INOmax is administered at doses >20 ppm, doses above this level ordinarily should not be used.
`
`
`Administration
`2.2
`The nitric oxide delivery systems used in the clinical trials provided operator-determined
`concentrations of nitric oxide in the breathing gas, and the concentration was constant throughout
`the respiratory cycle. INOmax must be delivered through a system with these characteristics and
`which does not cause generation of excessive inhaled nitrogen dioxide. The INOvent® system
`and other systems meeting these criteria were used in the clinical trials. In the ventilated neonate,
`precise monitoring of inspired nitric oxide and NO2 should be instituted, using a properly
`calibrated analysis device with alarms. The system should be calibrated using a precisely defined
`calibration mixture of nitric oxide and nitrogen dioxide, such as INOcal®. Sample gas for
`analysis should be drawn before the Y-piece, proximal to the patient. Oxygen levels should also
`be measured.
`
`In the event of a system failure or a wall-outlet power failure, a backup battery power supply and
`reserve nitric oxide delivery system should be available.
`
`Do not discontinue INOmax abruptly, as it may result in an increase in pulmonary artery
`pressure (PAP) and/or worsening of blood oxygenation (PaO2). Deterioration in oxygenation and
`elevation in PAP may also occur in children with no apparent response to INOmax.
`Discontinue/wean cautiously.
`
` 3
`
`DOSAGE FORMS AND STRENGTHS
`
`Nitric oxide is a gas available in 100 ppm and 800 ppm concentrations.
`
` 4
`
`CONTRAINDICATIONS
`
`INOmax is contraindicated in the treatment of neonates known to be dependent on right-to-left
`shunting of blood.
`
`WARNINGS AND PRECAUTIONS
`
` 5
`
`
`
`
`
`Reference ID: 2881485
`
`

`

`Rebound
`5.1
`Abrupt discontinuation of INOmax may lead to worsening oxygenation and increasing
`pulmonary artery pressure.
`
`
`
`Methemoglobinemia
`5.2
`Methemoglobinemia increases with the dose of nitric oxide. In clinical trials, maximum
`methemoglobin levels usually were reached approximately 8 hours after initiation of inhalation,
`although methemoglobin levels have peaked as late as 40 hours following initiation of INOmax
`therapy. In one study, 13 of 37 (35%) of neonates treated with INOmax 80 ppm had
`methemoglobin levels exceeding 7%. Following discontinuation or reduction of nitric oxide, the
`methemoglobin levels returned to baseline over a period of hours.
`
`
`
`Elevated NO2 Levels
`5.3
`In one study, NO2 levels were <0.5 ppm when neonates were treated with placebo, 5 ppm, and
`20 ppm nitric oxide over the first 48 hours. The 80 ppm group had a mean peak NO2 level of 2.6
`ppm.
`
`5.4 Heart Failure
`Patients who had pre-existing left ventricular dysfunction treated with inhaled nitric oxide, even
`for short durations, experienced serious adverse events (e.g., pulmonary edema).
`
`ADVERSE REACTIONS
`
` 6
`
`
`
`
`Because clinical trials are conducted under widely varying conditions, adverse reaction rates
`observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials
`of another drug and may not reflect the rates observed in practice. The adverse reaction
`information from the clinical studies does, however, provide a basis for identifying the adverse
`events that appear to be related to drug use and for approximating rates.
`
`
`Clinical Trials Experience
`6.1
`Controlled studies have included 325 patients on INOmax doses of 5 to 80 ppm and 251 patients
`on placebo. Total mortality in the pooled trials was 11% on placebo and 9% on INOmax, a result
`adequate to exclude INOmax mortality being more than 40% worse than placebo.
`
`
`Reference ID: 2881485
`
`

`

`In both the NINOS and CINRGI studies, the duration of hospitalization was similar in INOmax
`and placebo-treated groups.
`
`From all controlled studies, at least 6 months of follow-up is available for 278 patients who
`received INOmax and 212 patients who received placebo. Among these patients, there was no
`evidence of an adverse effect of treatment on the need for rehospitalization, special medical
`services, pulmonary disease, or neurological sequelae.
`
`In the NINOS study, treatment groups were similar with respect to the incidence and severity of
`intracranial hemorrhage, Grade IV hemorrhage, periventricular leukomalacia, cerebral infarction,
`seizures requiring anticonvulsant therapy, pulmonary hemorrhage, or gastrointestinal
`hemorrhage.
`
`
`The table below shows adverse reactions that occurred in at least 5% of patients receiving
`INOmax in the CINRGI study with event rates >5% and greater than placebo event rates. None
`of the differences in these adverse reactions were statistically significant when inhaled nitric
`oxide patients were compared to patients receiving placebo.
`
`Table 1:
`Adverse Event
`
`Adverse Reactions in the CINRGI Study
`Placebo (n=89)
`
`Inhaled NO
`(n=97)
`13 (13%)
`12 (12%)
`9 (9%)
`8 (8%)
`8 (8%)
`7 (7%)
`6 (6%)
`5 (5%)
`5 (5%)
`
`Hypotension
`Withdrawal
`Atelectasis
`Hematuria
`Hyperglycemia
`Sepsis
`Infection
`Stridor
`Cellulitis
`
`
`
`9 (10%)
`9 (10%)
`8 (9%)
`5 (6%)
`6 (7%)
`2 (2%)
`3 (3%)
`3 (3%)
`0 (0%)
`
`Post-Marketing Experience
`6.2
`The following adverse reactions have been identified during post-approval use of INOmax.
`Because these reactions are reported voluntarily from a population of uncertain size, it is not
`always possible to estimate their frequency reliably or to establish a causal relationship to drug
`
`Reference ID: 2881485
`
`

`

`exposure. The listing is alphabetical: dose errors associated with the delivery system; headaches
`associated with environmental exposure of INOmax in hospital staff; hypotension associated
`with acute withdrawal of the drug; hypoxemia associated with acute withdrawal of the drug;
`pulmonary edema in patients with CREST syndrome.
`
`DRUG INTERACTIONS
`
` 7
`
`
`
`
`No formal drug-interaction studies have been performed, and a clinically significant interaction
`with other medications used in the treatment of hypoxic respiratory failure cannot be excluded
`based on the available data. INOmax has been administered with tolazoline, dopamine,
`dobutamine, steroids, surfactant, and high-frequency ventilation. Although there are no study
`data to evaluate the possibility, nitric oxide donor compounds, including sodium nitroprusside
`and nitroglycerin, may have an additive effect with INOmax on the risk of developing
`methemoglobinemia. An association between prilocaine and an increased risk of
`methemoglobinemia, particularly in infants, has specifically been described in a literature case
`report. This risk is present whether the drugs are administered as oral, parenteral, or topical
`formulations.
`
`USE IN SPECIFIC POPULATIONS
`
` 8
`
`
`
`
`
`Pregnancy
`8.1
`Pregnancy Category C
`Animal reproduction studies have not been conducted with INOmax. It is not known if INOmax
`can cause fetal harm when administered to a pregnant woman or can affect reproductive
`capacity. INOmax is not intended for adults.
`
`
`8.2
`Labor and Delivery
`The effect of INOmax on labor and delivery in humans is unknown.
`
`
`
`Nursing Mothers
`8.3
`Nitric oxide is not indicated for use in the adult population, including nursing mothers. It is not
`known whether nitric oxide is excreted in human milk.
`
`Reference ID: 2881485
`
`

`

`Formatted: Font: Italic
`
`Formatted: Font: Italic
`
`
`
`Pediatric Use
`8.4
`The safety and efficacy of nitric oxide for inhalation has been demonstrated in term and near-
`term neonates with hypoxic respiratory failure associated with evidence of pulmonary
`hypertension [see Clinical Studies (14.1)]. Additional studies conducted in premature neonates
`for the prevention of bronchopulmonary dysplasia have not demonstrated substantial evidence of
`efficacy [see Clinical Studies (14.3)].Nitric oxide for inhalation has been studied in neonatal
`populations for the treatment of hypoxic respiratory failure and for the prevention of
`bronchopulmonary dysplasia [see Clinical Studies (14.1, 14.3)]. No information about its
`effectiveness in other age populations is available.
`
`
`Geriatric Use
`8.5
`Nitric oxide is not indicated for use in the adult population.
`
`
`OVERDOSAGE
`
`10
`
`Overdosage with INOmax will be manifest by elevations in methemoglobin and pulmonary
`toxicities associated with inspired NO2. Elevated NO2 may cause acute lung injury. Elevations in
`methemoglobinemia reduce the oxygen delivery capacity of the circulation. In clinical studies,
`NO2 levels >3 ppm or methemoglobin levels >7% were treated by reducing the dose of, or
`discontinuing, INOmax.
`
`Methemoglobinemia that does not resolve after reduction or discontinuation of therapy can be
`treated with intravenous vitamin C, intravenous methylene blue, or blood transfusion, based
`upon the clinical situation.
`
`
`
`DESCRIPTION
`
`11
`
`INOmax (nitric oxide gas) is a drug administered by inhalation. Nitric oxide, the active substance
`in INOmax, is a pulmonary vasodilator. INOmax is a gaseous blend of nitric oxide and nitrogen
`(0.08% and 99.92%, respectively for 800 ppm; 0.01% and 99.99%, respectively for 100 ppm).
`INOmax is supplied in aluminum cylinders as a compressed gas under high pressure (2000
`pounds per square inch gauge [psig]).
`The structural formula of nitric oxide (NO) is shown below:
`
`Reference ID: 2881485
`
`

`

`
`
`12
`
`
`
`CLINICAL PHARMACOLOGY
`
`Mechanism of Action
`12.1.
`Nitric oxide is a compound produced by many cells of the body. It relaxes vascular smooth
`muscle by binding to the heme moiety of cytosolic guanylate cyclase, activating guanylate
`cyclase and increasing intracellular levels of cyclic guanosine 3',5'-monophosphate, which then
`leads to vasodilation. When inhaled, nitric oxide selectively dilates the pulmonary vasculature,
`and because of efficient scavenging by hemoglobin, has minimal effect on the systemic
`vasculature.
`
`INOmax appears to increase the partial pressure of arterial oxygen (PaO2) by dilating pulmonary
`vessels in better ventilated areas of the lung, redistributing pulmonary blood flow away from
`lung regions with low ventilation/perfusion (V/Q) ratios toward regions with normal ratios.
`
`
`Pharmacodynamics
`12.2.
`Effects on Pulmonary Vascular Tone in PPHN
`Persistent pulmonary hypertension of the newborn (PPHN) occurs as a primary developmental
`defect or as a condition secondary to other diseases such as meconium aspiration syndrome
`(MAS), pneumonia, sepsis, hyaline membrane disease, congenital diaphragmatic hernia (CDH),
`and pulmonary hypoplasia. In these states, pulmonary vascular resistance (PVR) is high, which
`results in hypoxemia secondary to right-to-left shunting of blood through the patent ductus
`arteriosus and foramen ovale. In neonates with PPHN, INOmax improves oxygenation (as
`indicated by significant increases in PaO2).
`
`
`12.3.
`Pharmacokinetics
`The pharmacokinetics of nitric oxide has been studied in adults.
`
`
`
`Pharmacokinetics: Uptake and Distribution
`12.4
`Nitric oxide is absorbed systemically after inhalation. Most of it traverses the pulmonary
`capillary bed where it combines with hemoglobin that is 60% to 100% oxygen-saturated. At this
`level of oxygen saturation, nitric oxide combines predominantly with oxyhemoglobin to produce
`methemoglobin and nitrate. At low oxygen saturation, nitric oxide can combine with
`deoxyhemoglobin to transiently form nitrosylhemoglobin, which is converted to nitrogen oxides
`and methemoglobin upon exposure to oxygen. Within the pulmonary system, nitric oxide can
`
`Reference ID: 2881485
`
`

`

`combine with oxygen and water to produce nitrogen dioxide and nitrite, respectively, which
`interact with oxyhemoglobin to produce methemoglobin and nitrate. Thus, the end products of
`nitric oxide that enter the systemic circulation are predominantly methemoglobin and nitrate.
`
`
`Pharmacokinetics: Metabolism
`12.5
`Methemoglobin disposition has been investigated as a function of time and nitric oxide exposure
`concentration in neonates with respiratory failure. The methemoglobin (MetHb) concentration-
`time profiles during the first 12 hours of exposure to 0, 5, 20, and 80 ppm INOmax are shown in
`Figure 1.
`
`Figure 1: Methemoglobin Concentration-Time Profiles Neonates Inhaling
`0, 5, 20 or 80 ppm INOmax
`
`
`
`Methemoglobin concentrations increased during the first 8 hours of nitric oxide exposure. The
`mean methemoglobin level remained below 1% in the placebo group and in the 5 ppm and 20
`ppm INOmax groups, but reached approximately 5% in the 80 ppm INOmax group.
`Methemoglobin levels >7% were attained only in patients receiving 80 ppm, where they
`comprised 35% of the group. The average time to reach peak methemoglobin was 10 ± 9 (SD)
`hours (median, 8 hours) in these 13 patients, but one patient did not exceed 7% until 40 hours.
`
`
`Pharmacokinetics: Elimination
`12.6
`Nitrate has been identified as the predominant nitric oxide metabolite excreted in the urine,
`accounting for >70% of the nitric oxide dose inhaled. Nitrate is cleared from the plasma by the
`kidney at rates approaching the rate of glomerular filtration.
`
`
`Reference ID: 2881485
`
`

`

`NONCLINICAL TOXICOLOGY
`
`13
`
`
`
`Carcinogenesis, Mutagenesis, Impairment of Fertility
`13.1.
`No evidence of a carcinogenic effect was apparent, at inhalation exposures up to the
`recommended dose (20 ppm), in rats for 20 hr/day for up to two years. Higher exposures have
`not been investigated.
`Nitric oxide has demonstrated genotoxicity in Salmonella (Ames Test), human lymphocytes, and
`after in vivo exposure in rats. There are no animal or human studies to evaluate nitric oxide for
`effects on fertility.
`
`
`
`14
`
`
`
`CLINICAL STUDIES
`
`Treatment of Hypoxic Respiratory Failure (HRF)
`14.1
`The efficacy of INOmax has been investigated in term and near-term newborns with hypoxic
`respiratory failure resulting from a variety of etiologies. Inhalation of INOmax reduces the
`oxygenation index (OI= mean airway pressure in cm H2O × fraction of inspired oxygen
`concentration [FiO2]× 100 divided by systemic arterial concentration in mm Hg [PaO2]) and
`increases PaO2 [see Clinical Pharmacology (12.1)].
`
`NINOS Study
`The Neonatal Inhaled Nitric Oxide Study (NINOS) group conducted a double-blind, randomized,
`placebo-controlled, multicenter trial in 235 neonates with hypoxic respiratory failure. The
`objective of the study was to determine whether inhaled nitric oxide would reduce the occurrence
`of death and/or initiation of extracorporeal membrane oxygenation (ECMO) in a prospectively
`defined cohort of term or near-term neonates with hypoxic respiratory failure unresponsive to
`conventional therapy. Hypoxic respiratory failure was caused by meconium aspiration syndrome
`(MAS; 49%), pneumonia/sepsis (21%), idiopathic primary pulmonary hypertension of the
`newborn (PPHN; 17%), or respiratory distress syndrome (RDS; 11%). Infants ≤14 days of age
`(mean, 1.7 days) with a mean PaO2 of 46 mm Hg and a mean oxygenation index (OI) of 43 cm
`H2O / mm Hg were initially randomized to receive 100% O2 with (n=114) or without (n=121) 20
`ppm nitric oxide for up to 14 days. Response to study drug was defined as a change from
`baseline in PaO2 30 minutes after starting treatment (full response = >20 mm Hg, partial = 10–20
`mm Hg, no response = <10 mm Hg). Neonates with a less than full response were evaluated for a
`response to 80 ppm nitric oxide or control gas. The primary results from the NINOS study are
`presented in Table 2.
`
`
`Reference ID: 2881485
`
`

`

`Table 2:
`
`
`P value
`
`0.006
`0.60
`0.014
`
`Summary of Clinical Results from NINOS Study
`Control
`NO
`(n=121)
`(n=114)
`Death or ECMO*,†
`77 (64%)
`52 (46%)
`20 (17%)
`16 (14%)
`Death
`66 (55%)
`44 (39%)
`ECMO
`* Extracorporeal membrane oxygenation
`† Death or need for ECMO was the study's primary end point
`
`Although the incidence of death by 120 days of age was similar in both groups (NO, 14%;
`control, 17%), significantly fewer infants in the nitric oxide group required ECMO compared
`with controls (39% vs. 55%, p = 0.014). The combined incidence of death and/or initiation of
`ECMO showed a significant advantage for the nitric oxide treated group (46% vs. 64%, p =
`0.006). The nitric oxide group also had significantly greater increases in PaO2 and greater
`decreases in the OI and the alveolar-arterial oxygen gradient than the control group (p<0.001 for
`all parameters). Significantly more patients had at least a partial response to the initial
`administration of study drug in the nitric oxide group (66%) than the control group (26%,
`p<0.001). Of the 125 infants who did not respond to 20 ppm nitric oxide or control, similar
`percentages of NO-treated (18%) and control (20%) patients had at least a partial response to 80
`ppm nitric oxide for inhalation or control drug, suggesting a lack of additional benefit for the
`higher dose of nitric oxide. No infant had study drug discontinued for toxicity. Inhaled nitric
`oxide had no detectable effect on mortality. The adverse events collected in the NINOS trial
`occurred at similar incidence rates in both treatment groups [see Adverse Reactions (6.1)].
`Follow-up exams were performed at 18–24 months for the infants enrolled in this trial. In the
`infants with available follow-up, the two treatment groups were similar with respect to their
`mental, motor, audiologic, or neurologic evaluations.
`
`CINRGI Study
`This study was a double-blind, randomized, placebo-controlled, multicenter trial of 186 term and
`near-term neonates with pulmonary hypertension and hypoxic respiratory failure. The primary
`objective of the study was to determine whether INOmax would reduce the receipt of ECMO in
`these patients. Hypoxic respiratory failure was caused by MAS (35%), idiopathic PPHN (30%),
`pneumonia/sepsis (24%), or RDS (8%). Patients with a mean PaO2 of 54 mm Hg and a mean OI
`of 44 cm H2O / mm Hg were randomly assigned to receive either 20 ppm INOmax (n=97) or
`nitrogen gas (placebo; n=89) in addition to their ventilatory support. Patients who exhibited a
`PaO2 >60 mm Hg and a pH < 7.55 were weaned to 5 ppm INOmax or placebo. The primary
`results from the CINRGI study are presented in Table 3.
`
`
`Reference ID: 2881485
`
`

`

`P value
`<0.001
`0.48
`
`Summary of Clinical Results from CINRGI Study
`Table 3:
`Placebo
`INOmax
`
`ECMO*,†
`51/89 (57%)
`30/97 (31%)
`5/89 (6%)
`3/97 (3%)
`Death
`* Extracorporeal membrane oxygenation
`† ECMO was the primary end point of this study
`
`Significantly fewer neonates in the INOmax group required ECMO compared to the control
`group (31% vs. 57%, p<0.001). While the number of deaths were similar in both groups
`(INOmax, 3%; placebo, 6%), the combined incidence of death and/or receipt of ECMO was
`decreased in the INOmax group (33% vs. 58%, p<0.001).
`
`In addition, the INOmax group had significantly improved oxygenation as measured by PaO2,
`OI, and alveolar-arterial gradient (p<0.001 for all parameters). Of the 97 patients treated with
`INOmax, 2 (2%) were withdrawn from study drug due to methemoglobin levels >4%. The
`frequency and number of adverse events reported were similar in the two study groups [see
`Adverse Reactions (6.1)].
`
`
`
`Ineffective in Adult Respiratory Distress Syndrome (ARDS)
`14.2
`ARDS Study
`In a randomized, double-blind, parallel, multicenter study, 385 patients with adult respiratory
`distress syndrome (ARDS) associated with pneumonia (46%), surgery (33%), multiple trauma
`(26%), aspiration (23%), pulmonary contusion (18%), and other causes, with PaO2/FiO2 <250
`mm Hg despite optimal oxygenation and ventilation, received placebo (n=193) or INOmax
`(n=192), 5 ppm, for 4 hours to 28 days or until weaned because of improvements in oxygenation.
`Despite acute improvements in oxygenation, there was no effect of INOmax on the primary
`endpoint of days alive and off ventilator support. These results were consistent with outcome
`data from a smaller dose ranging study of nitric oxide (1.25 to 80 ppm). INOmax is not indicated
`for use in ARDS.
`
`
`Ineffective in Prevention of Bronchopulmonary Dysplasia (BPD)
`14.3
`The safety and efficacy of INOmax for the prevention of chronic lung disease
`[bronchopulmonary dysplasia, (BPD)] in neonates ≤ 34 weeks gestational age requiring
`respiratory support has been studied in three large, multi-center, double-blind, placebo-controlled
`clinical trials in a total of 2,149 preterm infants.1,2,3 Of these, 1,068 received placebo, and 1,081
`received inhaled nitric oxide at doses ranging from 5-20 ppm, for treatment periods of 7-24 days
`duration. The primary endpoint for these studies was alive and without BPD at 36 weeks
`postmenstrual age (PMA). The need for supplemental oxygen at 36 weeks PMA served as a
`
`Reference ID: 2881485
`
`

`

`surrogate endpoint for the presence of BPD. Overall, efficacy for the prevention of
`bronchopulmonary dysplasia in preterm infants was not established. There were no meaningful
`differences between treatment groups with regard to deaths, methemoglobin levels, or adverse
`events commonly observed in premature infants, including intraventricular hemorrhage, patent
`ductus arteriosus, pulmonary hemorrhage, and retinopathy of prematurity. The use of INOmax
`for prevention of BPD in preterm neonates ≤ 34 weeks gestational age is not indicated.
`
`
`REFERENCES
`
`15.
`
`1Kinsella JP, Cutter GR, Walsh WF, Gerstmann DR, Bose CL, Hart C, et al. Early inhaled nitric oxide therapy in
`premature newborns with respiratory failure. N Engl J Med 2006 Jul 27;355(4):354-64.
`2Ballard RA, Truog WE, Cnaan A, Martin RJ, Ballard PL, Merrill JD, et al. Inhaled nitric oxide in preterm infants
`undergoing mechanical ventilation. N Engl J Med 2006 Jul 27;355(4):343-53.
`3Mercier JC, Hummler H, Durrmeyer X, Sanchez-Luna M, Carnielli V, Field D, et al. Inhaled nitric oxide for
`prevention of bronchopulmonary dysplasia in premature babies (EUNO): a randomised controlled trial. Lancet 2010
`Jul 31;376(9738):346-54.
`
`
`HOW SUPPLIED/STORAGE AND HANDLING
`
`16
`
`INOmax (nitric oxide) is available in the following sizes:
`Size D
`Portable aluminum cylinders containing 353 liters at STP of nitric oxide gas
`in 800 ppm concentration in nitrogen (delivered volume 344 liters) (NDC
`64693-002-01)
`Portable aluminum cylinders containing 353 liters at STP of nitric oxide gas
`in 100 ppm concentration in nitrogen (delivered volume 344 liters) (NDC
`64693-001-01)
`Aluminum cylinders containing 1963 liters at STP of nitric oxide gas in 800
`ppm concentration in nitrogen (delivered volume 1918 liters) (NDC 64693-
`002-02)
`Aluminum cylinders containing 1963 liters at STP of nitric oxide gas in 100
`ppm concentration in nitrogen (delivered volume 1918 liters) (NDC 64693-
`001-02)
`
`Size D
`
`Size 88
`
`Size 88
`
`
`Store at 25°C (77°F) with excursions permitted between 15–30°C (59–86°F) [see USP
`Controlled Room Temperature].
`
`Reference ID: 2881485
`
`

`

`
`Occupational Exposure
`The exposure limit set by the Occupational Safety and Health Administration (OSHA) for nitric
`oxide is 25 ppm, and for NO2 the limit is 5 ppm.
`
`INO Therapeutics
`6 Route 173 West
`Clinton, NJ 08809
`USA
`© 2010 INO Therapeutics
`
`Reference ID: 2881485
`
`